A Phase I/II dose escalation study of 90Y-murine anti-CD20 monoclonal antibody (MAB) in patients with recurrent B cell lymphoma was completed. The primary objectives of the study were to: 1) determine the effect of the preinfusion of unlabeled anti-CD20 MAB on the biodistribution, pharmacokinetics, clearance and tumor uptake of 111In-anti-CD20 MAB, 2) determine the maximal tolerated dose of 90Y-anti-CD20 MAB that does not require bone marrow transplantation, and 3) evaluate the safety and anti-tumor effect of 90Y-anti-CD20 MAB in patients with recurrent B cell lymphoma. Eighteen patients (6 women, 12 men); ages 38-69 yrs) with relapsed low or intermediate-grade non-Hodgkin's lymphoma that had failed at least one course of conventional chemotherapy were treated. Biodistribution studies with 111In-anti-CD20 MAB were performed prior to therapy using either 0, 1, or 2.5 mg/kg of unlabeled MAB prior to administration of 111In-MAB. Since preinfusion of unlabeled MAB generally resulted in improved MAB biodistribution and imaging of known sites of disease, unlabeled anti-CD20 MAB (1 or 2.5mg/kg) was similarly infused prior to administration of the 90Y-anti-CD20. Groups of 304 patients were treated at dose levels of approximately 13.5, 20, 30, 40, and 50 mCi 90Y-anti-CD20 MAB. Three patients were retreated at the 40 mCi dose level. The use of unlabeled antibody favorably affected the biodistribution primarily by decreasing splenic uptake and urinary excretion while increasing the relative uptake in disease sites. Non-hematological toxicity was minimal. The only significant toxicity was myelosuppression which required reinfusion of peripheral stem cells in two of the four patients treated with 50 mCi 90Y-anti-CD20, and infection or fever and neutropenia (no source) following therapy in 33% of the patients treated with a single dose of 90Y-anti-CD20 MAB and two of three patients retreated with 40 mCi 90Y-anti-CD20 MAB. Three of the patients have developed a human anti-mouse antibody response. The overall response rate following a single dose of 90Y-anti-CD20 MAB therapy was 72% with six complete responses and seven partial responses. Nine of these responses (including two retreated patients) are ongoing with freedom from progression of 4+ to 29+ months following treatment. In summary, radioimmunotherapy with more than 50 mCi 90Y-anti-CD20 MAB resulted in minimal non-hematological toxicity and durable clinical responses in patients with recurrent B cell lymphoma. Doses of less than 40 mCi 90Y-anti-CD20 MAB were not myeloablative and preinfusion of unlabeled anti-CD20 MAB resulted in improved MAB biodistribution.